Researchers representing the University of Pittsburgh and two institutions in South Africa, the University of Cape Town and the University of Stellenbosch are seeking funds as part of an overall effort between our institutions to examine a specific hypothesis pertaining to the impact of environment on brain and behavior and also to help create within the academic community in Cape Town a regional center of excellence in neuroscience and in professional skill training. Their hypothesis is that exposure of developing animals to severe stress will have a significant detrimental effect on brain and increase its vulnerability to neuronal death, but that this can be offset through an exercise intervention program. There are five specific aims: four are research aims and one is a set of capacity building objectives. Research objectives: Aim 1 - To examine the impact of a developmental stressor (maternal separation) on several variables related to the vulnerability of the brain, including (a) the hypothalamic-pituitary-adrenal (HPA) axis, (b) mitochondrial function, and (c) alterations in a specific class of proteins (neurotrophic factors) by using a proteomic screen. Aim 2 - In addition, the state of central dopamine neurons will be carefully examined. Aim 3 - To examine the effects of exercise (voluntary running) on these same variables, and then to determine whether the effect of maternal separation can be offset by later exposure to exercise. Aim 4 -To examine the effects of maternal separation on the vulnerability of dopaminergic neurons to oxidative stress using 6- hydroxydopamine as the stressor, then determine whether any increase in vulnerability caused by the maternal separation can be offset by exercise. Aim 5 - Capacity building objectives: To further develop the research capacity of the Universities of Cape Town and Stellenbosch as well as other institutions in the Western Cape through attendance by faculty and trainees at international meetings, participation in specific courses on research methodology, and provision of instruction in other professional skills, such as oral and written communication, applying for research funds, and responsible conduct of research. The research team believes that their research project will provide important insights into epigenetic influences on behavior and brain function more generally, and also serve as a context for promoting the research capacity of two key institutions in southern Africa.